Summary of work: Although the incidence of cancer increases with age, tumors of the prostate, breast, and ovary grow more slowly and progression is less aggressive in the elderly, perhaps because of changes in tumor vasculature. However, adequate animal models to study these processes have not been available. Several transplantable mouse tumor models are being used to identify factors which may contribute to inhibition of tumor growth in aged animals. These factors are being tested in human prostate and rat breast tumor models in an effort to identify the source(s) of tumor growth inhibition with age. We have developed a simple, in vivo quantitative assay to measure vascularization and assess angiogenic and potential anti-angiogenic factors. Using this assay, collaborative studies with the Laboratory of Cardiovascular Sciences showed that adenoviral vectors overexpressing the p53 tumor suppressor gene inhibited endothelial cell differentiation in culture and angiogenesis in vivo. Endothelial cell death was not observed. However, p53 overexpression activated human prostate tumor cell apoptosis in vitro and resulted in tumor regression in nude mice. Recent studies to examine vascular endothelial cell death showed that protein tyrosine phosphatases are activated during apoptosis. DNA fragmentation, as detected by Tunel staining and laddering, loss of actin filaments, activation of TRPM-2 gene expression, and characteristic morphological changes all indicated an apoptotic form of cell death which could be prevented with inhibitors of tyrosine phosphatases. The Erk MAP kinase pathway was involved in preventing apoptosis even in the absence of proliferative effects and the cyclin-dependent kinase inhibitor p21 was found to be associated with differentiation and survival of the cells. The bcl-2 family of genes is being investigated for their role in preventing apoptosis and the activity of nuclear factor-kB in differentiation of endothelial cells is also being examined.